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Study Reveals Weight Loss Drug’s Effect on the Brain

Results suggests drug could particularly benefit “emotional eaters”

BOSTON – A weight-loss drug dampened the response to food cues in regions
of the brain associated with attention and emotion, leading to decreases in
caloric intake, weight and body mass index (BMI), a team led by scientists
at Beth Israel Deaconess Medical Center (BIDMC) reported. In the first
study of the drug lorcaserin in the human brain, the research revealed the
mechanism underlying the drug’s efficacy and provides insight into which
individuals may benefit most from the medication. The paper was published
today in the journal Diabetes, the journal of the American Diabetes
Association.

“Human feeding behaviors involve areas of the brain responsible for
cognitive control and decision-making,” said Christos S. Mantzoros, MD,
Director of the Human Nutrition Unit in the Division of Endocrinology,
Diabetes and Metabolism at BIDMC and Professor of Medicine at Harvard
Medical School. “We wanted to find out if lorcaserin was acting on these
brain regions and, if so, where and how. One-third of the U.S. population
is obese, and another one-third is overweight. This is a huge burden on
individuals and the health care system. In addition, it increases the risk
of diabetes, cardiovascular disease and many types of cancer. We need to
continue to develop safe and effective therapies to combat this epidemic.”

Approved by the FDA in 2012, the generic drug lorcaserin is a medication
prescribed for obese or overweight adults who also have weight-related
health complications such as diabetes. Several studies have shown the drug
helps about half of the people who take it lose more than 5 percent of
their body mass within a year, but there’s a great deal of variability in
individual results, and the mechanism underlying its effect was previously
unknown.

To determine how the drug works in the human brain, Mantzoros and
colleagues observed 48 obese men and women – half taking the drug, half
taking a placebo – over the course of a four-week experiment. Participants
came into the clinic on four occasions for blood work, physical exams,
measurements and weight-loss counseling with a registered dietician. They
were also expected to keep records of the food they ate during the study.

On three visits – before receiving any medication (Week 0), after a week of
medication (Week 1), and after four weeks of medication (Week 4) – exams
were followed by two brain scans: one after the patients had fasted for at
least 12 hours, the other after they had eaten a meal. The scans were taken
using functional magnetic resonance imaging (fMRI) to measure changes in
blood flow in an active brain, which suggests which regions play a role
during a given task. During each scan, participants were shown 150 images
of foods generally considered highly desirable, such as cake and onion
rings; foods generally considered less desirable like vegetables; and
nonfood items like rocks and trees.

At Week 1, the fMRI scans in the fasting state revealed that people taking
the drug showed decreased brain activity in response to images of highly
desirable foods in the attention-related parietal and visual cortices. At
Week 4, the lorcaserin group in the fed state showed less activity in the
parietal cortex – which is responsible for integrating sensory information
– when looking at any of the food images.

The data also revealed that subjects who had the strongest brain responses
to food prior to taking lorcaserin saw the most success with the
weight-loss medication.

“Decreases in caloric intake, weight, and BMI were linked to strong
responses to food cues in the areas of the brain related to emotion,
pleasure and attention prior to taking the weight-loss drug, which suggests
that lorcaserin could prove to be of particular benefit to ‘emotional
eaters,’ ” Mantzoros said.

Lorcaserin targets only a very specific serotonin receptor (known as
5-HT2c), shown in animal studies to play a role in abnormal food
consumption. A previous generation of weight loss drugs was linked to this
receptor, but because their scope was broader, those products also had dire
cardiac side effects including pulmonary hypertension and valve problems.
Lorcaserin could produce weight loss without these cardiac risks, the
authors noted.

“In addition, the different mechanism of action in comparison to other
drugs for obesity creates an opportunity for combination drugs for the
treatment of obesity,” Mantzoros said. “This might create more powerful
solutions and is something that remains to be explored.”

This work was funded by Harvard Clinical and Translational Science Center
Grant (UL1 RR025758) from the National Center for Research Resources.
Eisai, Inc. supported the study through an Investigator-Initiated Study
grant. Eisai approved the design of the study, but had no role in study
design; conduct of the study; collection, management, analysis, and
interpretation of the data; or the preparation, review, or approval of the
manuscript. Locaserin and placebo were provided by Arena Pharmaceuticals
GmbH through Eisai, Inc. This study is also supported in part by the
National Institutes of Health (DK081913). Olivia M. Farr was supported by
fellowship grant 5T32HD052961.

About Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding.

BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.